Obesity is associated with a low-grade inflammation which is correlated with an increased secretion of pro-inflammatory cytokines and chemokines by adipose tissue, suspected to contribute to the development of insulin resistance. Because lycopene is mostly stored in adipose tissue and possesses anti-inflammatory properties, we hypothesize that lycopene could reduce the production of proinflammatory markers in adipose tissue. In agreement with this hypothesis, we observed a decrease of inflammatory markers such as IL-6, MCP-1 and IL-1β at both the mRNA and protein level when explants of epididymal adipose tissue from mice fed with a high-fat diet were incubated with lycopene ex vivo. The same effect was reproduced with explants of adipose tissue preincubated in lycopene and then subjected to TNFα stimulation. The contribution of adipocytes and preadipocytes was evaluated. In both preadipocytes and differentiated 3T3-L1 adipocytes, lycopene preincubation for 24 h decreased the TNFα-mediated induction of IL-6 and MCP-1. Finally, the same results were reproduced with human adipocyte primary cultures. The molecular mechanism was also studied. In transient transfections, a decrease of the luciferase gene reporter under control of NF-κB responsive element was observed for cells incubated in the presence of lycopene and TNFα compared to TNFα alone. The involvement of the NF-κB pathway was confirmed by the modulation of IKKα/β phosphorylation by lycopene. Altogether, these results showed for the first time a limiting effect of lycopene on adipose tissue proinflammatory cytokine and chemokine production. Such an effect could prevent or limit the prevalence of obesity-associated pathologies, such as insulin resistance.